title: Catalytic versus inhibitory promiscuity in cytochrome P450s: implications for evolution of new function.
abstract: Catalytically promiscuous enzymes are intermediates in the evolution of new function from an existing pool of protein scaffolds. However, promiscuity will only confer an evolutionary advantage if other useful properties are not compromised or if there is no "negative trade-off" induced by the mutations that yield promiscuity. Therefore, identification and characterization of negative trade-offs incurred during the emergence of promiscuity are required to further develop the evolutionary models and to optimize in vitro evolution. One potential negative trade-off of catalytic promiscuity is increased susceptibility to inhibition, or inhibitory promiscuity. Here we exploit cytochrome P450s (CYPs) as a model protein scaffold that spans a vast range of catalytic promiscuity and apply a quantitative index to determine the relationship between promiscuity of catalysis and promiscuity of inhibition for a series of homologues. The aim of these studies is to begin to identify properties that, in general, correlate with catalytic promiscuity, hypothetically such as inhibitory promiscuity. Interestingly, the data indicate that the potential negative trade-off of inhibitory promiscuity is nearly insignificant because even highly substrate specific CYPs have high inhibitory promiscuity, with little incremental increase in susceptibility to inhibitory interactions as the substrate promiscuity increases across the series of enzymes. In the context of evolution, inhibitory promiscuity is not an obligate negative trade-off for catalytic promiscuity.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Amgen Inc., Seattle, Washington 98119, United States.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Foti
authors.forename: Mathew
authors.initials: M
authors.lastname: Honaker
authors.forename: Abhinav
authors.initials: A
authors.lastname: Nath
authors.forename: Josh T
authors.initials: JT
authors.lastname: Pearson
authors.forename: Brian
authors.initials: B
authors.lastname: Buttrick
authors.forename: Nina
authors.initials: N
authors.lastname: Isoherranen
authors.forename: William M
authors.initials: WM
authors.lastname: Atkins
mesh_terms: D055162:Biocatalysis; D055598:Chemical Phenomena; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D004347:Drug Interactions; D019143:Evolution, Molecular; D006801:Humans; D008099:Liver / Q000201:enzymology; D008861:Microsomes / Q000201:enzymology; D008954:Models, Biological; D008958:Models, Molecular; D011994:Recombinant Proteins / Q000378:metabolism; D013223:Statistics as Topic; D013379:Substrate Specificity
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System